It has been suggested that hydroxypropyl methyl cellulose acetate phthalate (HPMCAP) and hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT) may be used to form solid amorphous dispersions with low-solubility drugs, and that such dispersions should result in concentration enhancement (or improved bioavailability) of the drug in the dispersion in an aqueous environment of use. However, there has been no disclosure of the optimal degree of substitution of acetyl or phthalyl or trimellityl groups for either the HPMCAP or HPMCAT polymers.
The use of HPMCAP in physical admixtures with basic drugs has also been suggested for improving the bioavailability of such drugs. However, there has been no disclosure of the degree of substitution of acetyl or phthalyl groups for the HPMCAP polymer used in such admixtures.
Cellulose acetate succinate (CAS) was originally developed as an enteric polymer for coating pharmaceutical dosage forms. See U.S. Pat. No. 2,196,768. Enteric polymers are those that remain intact in the acidic environment of the stomach, preventing drug release therein, but degrade in the alkaline environment of the intestine so as to release drug in the intestine. Such polymers have also been used for matrix-type controlled-release dosage forms. See U.S. Pat. Nos. 4,652,442 and 4,795,641. However, there is no disclosure of the use of CAS for making a physical mixture or a solid dispersion of a low-solubility drug in either of these patents, nor is there any recognition of the impact of the degree of substitution (DOS) of the cellulose on the bioavailability of the drugs in such compositions.
U.S. Pat. No. 4,888,420 discloses the use of cellulose acetate and water-soluble derivatives thereof such as cellulose acetate phthalate and CAS to prepare highly porous microspheres that may be used as a carrier for controlled release of fragrances and drugs such as aspirin and prednisone. The '420 patent does not disclose the formation of physical mixtures or solid dispersions of CAS and a low-solubility drug, and although it does disclose a DOS of 0.5-1.0 for cellulose acetate, there is no disclosure of any particular DOS for any substituent group other than acetate, and there is no recognition of the impact of DOS on the bioavailability of drugs incorporated into the microspheres.
No reference has been found in the literature to methyl-substituted CAS (MCAS) in pharmaceutical applications.
Thus, while pharmaceutical formulations of drugs and HPMCAP, HPMCAT, and CAS polymers have been suggested, there has been no recognition of either the impact or Importance of the degrees of substitution of acetyl, phthalyl, trimellityl, succinyt, and methyl groups relative to enhancing the concentration of the drug in a use environment or improving the drug's bioavailability. What is desired therefore are HPMCAP, HPMCAT, CAS, and MCAS polymers specifically designed for improving the dissolved drug concentration in a pharmaceutical composition.